Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C271/34—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C335/04—Derivatives of thiourea
  • C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
  • C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
  • C07C335/12—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
  • C09K15/00—Anti-oxidant compositions; Compositions inhibiting chemical change
  • C09K15/04—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds
  • C09K15/20—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing nitrogen and oxygen
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
  • C09K15/00—Anti-oxidant compositions; Compositions inhibiting chemical change
  • C09K15/04—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds
  • C09K15/26—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing nitrogen and sulfur
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/52—Stabilizers
  • A61K2800/522—Antioxidants; Radical scavengers

Definitions

• the invention relates to 3,4-dihydroxybenzyl-substituted carbonic acid derivatives, to the preparation thereof and to the use thereof as antioxidants and/or free-radical scavengers, in particular in cosmetic and/or pharmaceutical preparations for protecting cells and tissue of humans and animals against the harmful effects of free radicals and reactive oxygen compounds which accelerate aging.
• the invention further relates to cosmetic and/or pharmaceutical preparations, and to foods and/or luxury products comprising these 3,4-dihydroxybenzyl-substituted carbonic acid derivatives.
• Ultraviolet light in particular ultraviolet light in the range from 290 to 400 nm, triggers photooxidative processes on and in the skin, in particular of humans and animals, various reactive oxygen compounds or free radicals being formed starting from oxygen. These may, for example, harm or destroy intracellular molecules and thus weaken the cell in its vitality or even cause it to die.
• the reactive oxygen compounds or free radicals can also damage the intracellular molecules or structures.
• the lipid layer which serves as a barrier against the environment, and also the sebum may be destroyed by oxidative processes.
• a major constituent of the vital sebum is considerably unsaturated squalene.
• Substances and preparations of these substances which, in physiological systems, support the natural defence mechanisms against free radicals and reactive oxygen compounds and/or, as antioxidants or free radical scavengers, protect the lipid layer of the skin against oxidative processes, safeguard the skin from destruction and aging.
• Such substances also protect oxygen-sensitive materials, such as oxidation-sensitive constituents of cosmetics, pharmaceuticals or foods and/or luxury products.
• Antioxidants are usually organic compounds which inhibit or prevent the undesired changes in the substances to be protected caused by oxygen effects and also oxidative processes (Römpp Lexikon Chemie 10th edition, 229 (1996)). Many antioxidants also function as free-radical scavengers and/or as complexing agents for heavy metal ions.
• the object of the present invention is to make available antioxidants with a strong specific free-radical scavenging and/or antioxidative action for use in cosmetic and pharmaceutical preparations, foods and luxury products, and for protecting cells and tissue of humans and animals.
• X 1 , X 2 and X 3 independently of one another, are oxygen atoms, sulfur atoms or groups —N—R 3 ,
• R 1 is a hydrogen atom, a lower alkyl, lower alkenyl, 1-oxo-lower alkyl or 1-oxo-lower alkenyl group having 1 to 5 carbon atoms or a group —O—R 4 , in which R 4 is a hydrogen atom, a lower alkyl, lower alkenyl, 1-oxo-lower alkyl or 1-oxo-lower alkenyl group having 1 to 5 carbon atoms,
• R 2 is a hydrogen atom, a branched or unbranched, cyclic or stretched alkyl or alkenyl group having 1 to 22 carbon atoms, where one or more of the carbon atoms may be replaced by oxygen atoms, or a ring-substituted arylalkyl group having 7 to 15 carbon atoms, with the proviso that the ring-substituted arylalkyl group does not contain halogen atoms,
• R 3 is a hydrogen atom, a branched or unbranched, cyclic or stretched alkyl or alkenyl group having 1 to 22 carbon atoms, where one or more of the carbon atoms may be replaced by oxygen atoms.
• EP A 0,068,592 and U.S. Pat. No. 4,443,473 describe aralkyl, alkyl or alkenyl carbamates and thiocarbamates of hydroxy-substituted benzylamines and corresponding pharmaceutical preparations, where the alkyl radicals can contain 3 to 12 carbon atoms.
• these specifications do not list any 3,4-dihydroxybenzyl-substituted carbonic acid derivatives.
• the synthesis of N-(2-(4-chlorophenyl)ethyl)-N′-(3,4-dihydroxybenzyl)thiourea has been described in J. Med. Chem., 1994, 37, pages 1942 to 1954. Further 3,4-dihydroxybenzyl-substituted carbonic acid derivatives are not known. Just as little with regard to the antioxidative or free-radical scavenging property of the compounds emerges from said specifications.
• novel 3,4-dihydroxybenzyl-substituted carbonic acid derivatives have, in comparison to known antioxidants, an excellent protective action on the skin of humans and animals against destruction and aging.
• the invention preferably relates to novel 3,4-dihydroxybenzyl-substituted carbonic acid derivatives of the general formula (Ia),
• R 1 is a hydrogen atom, a lower alkyl, lower alkenyl, 1-oxo-lower alkyl or 1-oxo-lower alkenyl group having 1 to 5 carbon atoms or a group —O—R 4 , in which R 4 is a hydrogen atom, a lower alkyl, lower alkenyl, 1-oxo-lower-alkyl or 1-oxo-lower-alkenyl group having 1 to 5 carbon atoms,
• X 1 is —NH
• X 2 and X 3 are oxygen, and
• R 2 is a hydrogen atom, a methyl, an ethyl or an ethenyl group.
• the invention further preferably relates to novel 3,4-dihydroxybenzyl-substituted carbonic acid derivatives of the general formula (Ib),
• R 1 is a hydrogen atom, a lower alkyl, lower alkenyl, 1-oxo-lower alkyl or 1-oxo-lower alkenyl group having 1 to 5 carbon atoms or a group —O—R 4 , in which R 4 is a hydrogen atom, a lower alkyl, lower alkenyl, 1-oxo-lower alkyl or 1-oxo-lower alkenyl group having 1 to 5 carbon atoms,
• X 1 is —NH
• X 2 and X 3 are oxygen
• R 2 is a branched or unbranched, cyclic or stretched alkyl or alkenyl group having 3 to 22 carbon atoms, where one or more of the carbon atoms may be replaced by oxygen atoms, or a ring-substituted arylalkyl group having 7 to 15 carbon atoms, with the proviso that the ring-substituted arylalkyl group does not contain halogen atoms.
• the invention further preferably relates to novel 3,4-dihydroxybenzyl-substituted carbonic acid derivatives of the general formula (Ic),
• R 1 is a hydrogen atom, a lower alkyl, lower alkenyl, 1-oxo-lower alkyl or 1-oxo-lower alkenyl group having 1 to 5 carbon atoms or a group —O—R 4 , in which R 4 is a hydrogen atom, a lower alkyl, lower alkenyl, 1-oxo-lower alkyl or 1-oxo-lower alkenyl group having 1 to 5 carbon atoms,
• X 1 , X 2 and X 3 independently of one another, are oxygen atoms, sulfur atoms or groups —NH, with the proviso that X 1 is not —NH at the same time as X 2 and X 3 are oxygen,
• R 2 is a branched or unbranched, cyclic or stretched alkyl or alkenyl group having 1 to 22 carbon atoms, where one or more of the carbon atoms may be replaced by oxygen atoms, or a ring-substituted arylalkyl group having 7 to 15 carbon atoms, with the proviso that the ring-substituted arylalkyl group does not contain halogen atoms.
• a lower alkyl group consists of 1 to 5 carbon atoms and may, for example, be: methyl, ethyl, 1-propyl, 2-propyl-, 1-butyl, 2-butyl, tert.-butyl, 2-methylprop-1-yl, cyclopropyl, cyclopropylmethyl, 2,2-dimethylcyclopropyl, cyclobutyl, 1-, 2- or 3-pentyl-, 2-methylbut-1-yl, 2-methylbut-2-yl, 3-methylbut-1-yl, 3-methylbut-2-yl or cyclopentyl.
• a lower alkenyl group consists of 2 to 5 carbon atoms and may, for example, be: ethenyl, prop-2-en-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, 1- or 2-cyclopropenyl-, but-1-en-1-yl, but-1-en-2-yl, but-1-en-3-yl, but-2-en-1-yl, but-3-en-1-yl, but-2-en-2-yl, 2-methylprop-1-en-1-yl, 2-methylprop-2-en-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, pent-1-en-1-yl, pent-1-en-2-yl, pent-1-en-3-yl, pent-1-en-4-yl, pent-2-en-1-yl, pent-2-en-2-yl, pent-2-en-3-yl, pent-2-en-4-yl, pent-2-
• a lower alkyl-1-oxo group consists of 1 to 5 carbon atoms and can, for example, be: formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2- or 3-methylbutanoyl, 2,2-dimethylpropanoyl, cyclopropylcarboxyl.
• a 1-oxoalkenyl group can contain 3 to 5 carbon atoms and may, for example, be: prop-2-enoyl, 2-methylprop-2-enoyl, 2-ethylprop-2-enoyl, E- or Z-2-butenoyl, 3-butenoyl, E- or Z-2-methylbut-2-enoyl, E- or Z-3-methylbut-2-enoyl, Z- or E-2-pentenoyl, Z- or E-3-pentenoyl.
• An unbranched, branched or cyclic alkyl group can contain 1 to 22, preferably 1 to 20, especially preferably 1 to 18, carbon atoms. Examples which may be mentioned are: methyl, ethyl, 1-propyl, 2-propyl-, 1-butyl, 2-butyl, tert.-butyl, 2-methyl, 2-methylprop-1-yl, cyclopropyl, cyclopropylmethyl, 2,2-dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and various positional isomers of methylpentyl, menthyl, 1-pentyl, 1-hexyl, 1-heptyl-, 1-octyl, 2-ethylhexyl, 1-nonyl, 1-decyl, 1-undecyl, 1-dodecyl, 1-tridecyl, 1-tetradecyl, 1-pentadecyl, 1-hex
• An unbranched, branched or cyclic alkenyl group can contain 2 to 22, preferably 2 to 20, especially preferably 2 to 18 carbon atoms. Examples which may be mentioned are: ethenyl, prop-2-en-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, 1- or 2-cyclopropenyl-, but-1-en-1-yl, but-1-en-2-yl, but-1-en-3-yl, but-2-en-1-yl, but-3-en-1-yl, but-2-en-2-yl, 2-methylprop-1-en-1-yl, 2-methylprop-2-en-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, pent-1-en-1-yl, pent-1-en-2-yl, pent-1-en-3-yl, pent-1-en-4-yl, pent-2-en-1-yl, pent-2-en-2-yl, pent-2-
• a ring-substituted arylalkyl group can consist of 7 to 15 carbon atoms, preferably of 7 to 8 carbon atoms, with the proviso that at least one further substituent on the aromatic moiety is not hydrogen. Particular preference is given to a ring-substituted benzyl, a 2- or 1-phenylethyl group.
• Substituents of the ring-substituted arylalkyl group may, for example, be: hydrogen atoms, lower alkyl, hydroxyl, lower alkyloxy, thio, lower alkylthio, amino, lower alkylamino, di-lower alkylamino, phosphate, lower alkylphosphate, di-lower alkylphosphate, sulfonic acid, lower alkylsulfonate, sulfonamide, di-lower alkylsulfonamide or lower alkylsulfonamide radicals.
• Particular preference is given to hydrogen atoms, lower alkyl, hydroxyl and lower alkyloxy radicals, with the proviso that the substituents are not halogen.
• R 1 is a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms or a group —O—R 4 , in which R 4 is a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms,
• X 1 is —NH
• X 2 and X 3 are oxygen, and
• R 2 is a hydrogen atom, a methyl, an ethyl or an ethenyl group.
• R 1 is a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms or a group —O—R 4 , in which R 4 is a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms,
• X 1 is —NH
• X 2 and X 3 are oxygen, and
• R 2 is a branched or unbranched, cyclic or stretched alkyl or alkenyl group having 3 to 20 carbon atoms, where one or more of the carbon atoms may be replaced by oxygen atoms, or a ring-substituted arylalkyl group having 7 to 8 carbon atoms, with the proviso that the ring-substituted arylalkyl group does not contain halogen atoms.
• X 1 and X 2 independently of one another, are oxygen atoms, sulfur atoms or —N—H,
• X 3 is an oxygen atom or a sulfur atom, with the proviso that X 1 is not —NH at the same time as X 2 and X 3 are oxygen
• R 1 is a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms or a group —O—R 4 , in which R 4 is a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms,
• R 2 is a branched or unbranched, cyclic or stretched alkyl or alkenyl group having 1 to 20 carbon atoms, where one or more of the carbon atoms may be replaced by oxygen atoms, or a ring-substituted arylalkyl group having 7 to 8 carbon atoms, with the proviso that the ring-substituted arylalkyl group does not contain halogen atoms.
• R 1 is a hydrogen atom, a methoxy or a hydroxyl group
• X 1 is —NH
• X 2 and X 3 are oxygen, and
• R 2 is a methyl, an ethyl or an ethenyl group.
• R 1 is a hydrogen atom, a methoxy or a hydroxyl group
• X 1 is —NH
• X 2 and X 3 are oxygen, and
• R 2 is a branched or unbranched, cyclic or stretched alkyl group having 3 to 18 carbon atoms, a branched or unbranched, cyclic or stretched alkenyl group having 3 to 18 carbon atoms or a ring-substituted benzyl, ring-substituted 2-phenylethyl or ring-substituted 1-phenylethyl radical, with the proviso that the ring-substituted arylalkyl group does not contain halogen atoms.
• R 1 is a hydrogen atom, a methoxy or a hydroxyl group
• X 1 is a group —N—H
• X 2 is an oxygen atom, sulfur atom or —N—H
• X 3 is an oxygen atom or a sulfur atom, with the proviso that X 2 and X 3 are not oxygen at the same time, and
• R 2 is a branched or unbranched, cyclic or stretched alkyl group having 1 to 18 carbon atoms, a branched or unbranched, cyclic or stretched alkenyl group having 2 to 18 carbon atoms or a ring-substituted benzyl, ring-substituted 2-phenylethyl or ring-substituted 1-phenylethyl radical, with the proviso that the ring-substituted arylalkyl group does not contain halogen atoms.
• the compounds according to the invention may also be present in the form of their tautomers.
• the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention are very good free-radical scavengers and particularly strong antioxidants. They are preferably suitable as antioxidants for lipids.
• the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention are able to suppress the harmful effects of free radicals and/or oxidative processes which are induced by UV light on and/or in human skin, and to support the natural antioxidative processes.
• the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention support, in physiological systems of the skin, the hair or the nails, the natural defence mechanisms against free radicals and reactive oxygen compounds and protect, in cosmetics, pharmaceuticals or foods, oxidation-sensitive constituents thereof against autoxidation or photooxidation.
• the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention can therefore be used in cosmetic or pharmaceutical, in particular cosmetic or dermatological, preparations for protecting cells and tissues of mammals, in particular of humans, against the harmful effect of free radicals and reactive oxygen species.
• the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention can of course also be used in other preparations, for example pharmaceutical preparations, preparations for protecting or influencing plants, in foods or luxury products or preparations for food supplements, or in other products, for example oxidation-sensitive natural or synthetic polymers (e.g. rubber, polyolefins), as antioxidants or free-radical scavengers.
• the amount of the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention in a cosmetic or pharmaceutical preparation is 0.001% by weight to 10% by weight, preferably 0.001 to 5% by weight, particularly preferably 0.001% by weight to 1% by weight, based on the total weight of the preparation.
• the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention can be synthesized using methods known per se, by reacting a 3,4-dihydroxybenzyl derivative of the general formula (II)
• X 1 is a group —O—H, —S—H, —NH 2 or —(NH 3 ) + , and
• R 1 has the meaning given above
• Y is a halogen atom, a group —N 3 , —O—N ⁇ C(C 6 H 5 )CN, —O—R 5 or —S—R 5 , and
• R 5 may be a lower alkyl, 1-oxo-lower alkyl, lower alkenyl, 1-oxo-lower alkenyl, aryl, arylalkyl, aryl-1-oxoalkyl or lower alkyloxycarbonyl group,
• X 4 is an oxygen atom or a sulfur atom
• R 2 has the meaning given above, or
• Z is a group —O—H, —S—H, —NH 2 or —(NH 3 ) + and
• R 2 has the meaning given above
• the particularly preferred 3,4-dihydroxybenzyl-substituted carbonic acid derivatives where X 1 is —N—H, X 2 and X 3 are in each case an oxygen atom and R 1 and R 2 have the meaning given above can be obtained, for example, by reacting a 3,4-dihydroxybenzylamine of the general formula (II), where X 1 is a group —NH 2 or —(NH 3 ) + and R 1 has the meaning given above, with a chloroformic ester of the general formula (III) where X 2 and X 3 are oxygen atoms, Y is a chlorine atom and R 2 has the meaning given above, in a solvent or solvent mixture, preferably chosen from the group consisting of water, acetone, 1,4-dioxane, tetrahydrofuran, various aliphatic esters of aliphatic alcohols (such as, for example, ethyl acetate), chlorine-containing solvents (e.g.
• auxiliary bases preferably chosen from the group of alkali metal hydroxides (e.g. NaOH), alkali metal carbonates (e.g. Na 2 CO 3 or NaHCO 3 ), alkaline earth metal hydroxyides (e.g. Mg(OH) 2 ), alkaline earth metal oxides (e.g. CaO) or alkaline earth metal carbonates (e.g. CaCO 3 ), ammonia, aliphatic amines (e.g. triethylamine or diisopropylamine), heterocyclic amines (e.g. pyridine or 4-(N,N-dimethylamino)pyridine) or basic inorganic or organic ion exchangers.
• alkali metal hydroxides e.g. NaOH
• alkali metal carbonates e.g. Na 2 CO 3 or NaHCO 3
• alkaline earth metal hydroxyides e.g. Mg(OH) 2
• alkaline earth metal oxides e.g. CaO
• the particularly preferred 3,4-dihydroxybenzyl-substituted carbonic acid derivatives of the general formula (Ic) where X 1 and X 2 are —N—H and X 3 is an oxygen or sulfur atom and R 1 and R 2 have the meaning given above can be obtained, for example, by reacting a 3,4-dihydroxybenzylamine of the general formula (II), where X 1 is a group —NH 2 or —(NH 3 ) + and R 1 has the meaning given above, with a heterocumulene of the general formula (IV), where X 4 and R 2 have the meanings given above, in a solvent or solvent mixture, preferably chosen from the group consisting of water, acetone, 1,4-dioxane, tetrahydrofuran, various aliphatic esters of aliphatic alcohols (such as, for example, ethyl acetate), chlorine-containing solvents (e.g.
• auxiliary bases preferably chosen from the group of alkali metal hydroxides (e.g. NaOH), alkali metal carbonates (e.g. Na 2 CO 3 or NaHCO 3 ), alkaline earth metal hydroxides (e.g. Mg(OH) 2 ), alkaline earth metal oxides (e.g. CaO) or alkaline earth metal carbonates (e.g. CaCO 3 ), ammonia, aliphatic amines (e.g. triethylamine or diisopropylamine) or heterocyclic amines (e.g. pyridine or 4-(N,N-dimethylamino)pyridine) or basic inorganic or organic ion exchangers.
• alkali metal hydroxides e.g. NaOH
• alkali metal carbonates e.g. Na 2 CO 3 or NaHCO 3
• alkaline earth metal hydroxides e.g. Mg(OH) 2
• alkaline earth metal oxides e.g. CaO
• a saponification step is advantageously connected downstream, in particular a basic saponification with one of the abovementioned bases in the abovementioned solvents or solvent mixtures, preferably water or water-containing solvent mixtures, at temperatures of from 30 to 130° C., preferably 50 to 100° C., in which the phenyl esters are selectively cleaved and the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives of the general formula (Ia) to (Ic) according to the invention are obtained in free form following adjustment of the pH to values of ⁇ 7, preferably with mineral acids (e.g. hydrochloric acid).
• mineral acids e.g. hydrochloric acid
• the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention can be further purified using methods known to the person skilled in the art, preferably crystallization, chromatographic methods or distillation.
• the 3,4-dihydroxybenzyl derivatives of the general formula (II) used are, in particular, 3,4-dihydroxybenzylamine or ammonium salts thereof, 3,4-dihydroxy-5-methylbenzylamine or ammonium salts thereof, 3,4-dihydroxy-5-methoxybenzylamine or ammonium salts thereof, 3,4,5-trihydroxybenzylamine or ammonium salts thereof, 3,4-dihydroxybenzyl alcohol or 3,4,5-trihydroxybenzyl alcohol.
• the activated carbonic acid derivatives of the general formula (III) used are preferably methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, chloroformic acid, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, di-tert-butyl pyrocarbonate, ( ⁇ )-menthyl chloroformate, n-hexyl chloroformate, 2-ethylhexyl chloroformate or other chloroformic esters of branched or unbranched, stretched or cyclic alkanols or alkenols.
• heterocumulenes of the general formula (IV) are preferably chosen from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, the various stretched or cyclic isomers of pentyl, hexyl, heptyl and octyl isothiocyanates or the corresponding isocyanates.
• the compounds of the general formula (V) are preferably chosen from the group consisting of methyl-, ethyl-, propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-, tert-butyl-, the various stretched or cyclic isomers of pentyl-, hexyl-, heptyl-, ring-substituted benzyl-, 1-phenylethyl- and 2-phenylethylamines, alcohols or thiols.
• the present invention also further relates to cosmetic and pharmaceutical preparations, in particular cosmetic and dermatological preparations which comprise the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention in an effective amount, alongside other, otherwise customary composition constituents.
• They comprise 0.001% by weight to 10% by weight, preferably 0.001 to 5% by weight, but in particular 0.001% by weight to 1% by weight, based on the total weight of the formulation, of the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention and may in this connection be in the form of “water-in-oil”, “oil-in-water”, “water-in-oil-in-water” or “oil-in-water-in-oil” emulsions, microemulsions, gels, solutions, e.g. in oils, alcohols or silicone oils, soaps, sticks, aerosols, sprays and also foams.
• compositions may be present in amounts of 5-99.999% by weight, preferably 10-80% by weight, based on the total weight of the formulation.
• formulations may comprise water in an amount up to 99.999% by weight, preferably 5-80% by weight, based on the total weight of the formulation.
• the cosmetic or dermatological preparations according to the invention are prepared using customary processes well known to the person skilled in the art, by incorporating one or more of the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention into cosmetic or dermatological formulations which have the customary composition and can be used for the treatment, protection, care and cleansing of the skin, nails or the hair and as make-up products in decorative cosmetics.
• the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention can also be incorporated beforehand into liposomes, e.g. starting from phosphatidylcholine, into microspheres, into nanospheres or else into capsules made of a suitable matrix, e.g. made of natural or synthetic waxes, for example beeswax, carnauba wax, silicone wax or paraffin waxes, and stearyl alcohol, eicosanol, cetyl alcohol, stearin or of gelatin.
• a suitable matrix e.g. made of natural or synthetic waxes, for example beeswax, carnauba wax, silicone wax or paraffin waxes, and stearyl alcohol, eicosanol, cetyl alcohol, stearin or of gelatin.
• the cosmetic and dermatological preparations according to the invention are applied to the skin, the nails and/or the hair in an adequate amount in the manner customary for cosmetics.
• the cosmetic and dermatological preparations according to the invention can comprise cosmetic auxiliaries and additives as are customarily used in such preparations, e.g. sunscreens (e.g. organic or inorganic light filter substances, preferably micropigments), preservatives, bactericides, fungicides, virucides, cooling active ingredients, plant extracts, antiinflammatory active ingredients, substances which accelerate wound healing (e.g. chitin or chitosan and derivatives thereof), film-forming substances (e.g. polyvinylpyrrolidones or chitosan or derivatives thereof), customary antioxidants, vitamins (e.g.
• sunscreens e.g. organic or inorganic light filter substances, preferably micropigments
• preservatives bactericides, fungicides, virucides
• cooling active ingredients e.g. chitin or chitosan and derivatives thereof
• film-forming substances e.g. polyvinylpyrrolidones or chitosan or derivatives
• vitamin C and derivatives tocopherols and derivatives, vitamin A and derivatives
• 2-hydroxycarboxylic acids e.g. citric acid, malic acid, L-, D-, or dl-lactic acid
• skin-lightening agents e.g. kojic acid, hydroquinone or arbutin
• skin-coloring agents e.g. walnut extracts or dihydroxyacetone
• perfumes antifoams, dyes, pigments which have a coloring action, thickeners, surface-active substances, emulsifiers, emollients, moisturizers and/or humectants (e.g. glycerol or urea), fats, oils, unsaturated fatty acids or derivatives thereof (e.g.
• linoleic acid ⁇ -linolenic acid, ⁇ -linolenic acid or arachidonic acid and natural or synthetic esters thereof in each case
• waxes or other customary constituents of a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents, silicone derivatives or chelating agents (e.g. ethylenediaminetetraacetic acid and derivatives).
• the preparations according to the invention can additionally also comprise other antioxidants.
• other antioxidants which can be used are all antioxidants customary or suitable for cosmetic and/or dermatological applications.
• the antioxidants are advantageously chosen from the group consisting of amino acids (e.g. glycine, histidine, 3,4-dihydroxyphenylalanine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g.
• urocaninic acid and derivatives thereof, peptides (D,L-carnosine, D-carnosine, L-carnosine, anserine) and derivatives thereof, carotenoids, carotenes (e.g. ⁇ -carotene, ⁇ -carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof, aurothioglucose, propylthiouracil and other thiols (e.g.
• thioredoxin glutathione, cysteine, cystine, cystamine and the glycosyl and N-acyl derivatives thereor or alkyl esters thereof), and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof, and phenolic acid amides of phenolic benzylamines (e.g.
• homovanillic acid amides 3,4-dihydroxyphenylacetic acid amides, ferulic acid amides, sinapic acid amides, caffeic acid amides, dihydroferulic acid amides, dihydrocaffeic acid amides, vanillomandelic acid amides or 3,4-dihydroxymandelic acid amides of 3,4-dihydroxybenzylamine, 2,3,4-trihydroxybenzylamine or 3,4,5-trihydroxybenzylamine), catecholoximes or catecholoxime ethers (e.g. 3,4-dihydroxybenzaldoxime or 3,4-dihydroxybenzaldehyde O-ethyloxime), and also (metal) chelating agents (e.g.
• gallic acid ferulic acid
• derivatives thereof e.g. propyl gallate, ethyl gallate, octyl gallate
• furfurylideneglucitol dibutylhydroxytoluene, butylhydroxyanisole
• uric acid and derivatives thereof mannose and derivatives thereof
• zinc and derivatives thereof e.g. ZnO, ZnSO 4
• selenium and derivatives thereof e.g. selenomethionine
• stilbenes and derivatives thereof e.g. stilbene oxide, resveratrol
• the amount of further antioxidants in the preparations according to the invention can generally be 0.001 to 30% by weight, preferably 0.001 to 20% by weight, particularly preferably 0.001 to 5% by weight, based on the total weight of the preparation.
• UV-A and/or UV-B filter substances where the total amount of filter substances may be 0.1 to 30% by weight, preferably 0.5 to 10% by weight, based on the total weight of the preparations, giving, for example, sunscreens for skin and hair.
• UV-A and/or UV-B filter substances which may be used are, for example, 3-benzylidenecamphor derivatives (e.g. 3-(4-methyl-benzylidene)-dl-camphor), aminobenzoic acid derivatives (e.g.
• polymer-bonded UV filters e.g. polymers of N-[2-(or 4)-(2-oxo-3-bornylidene)methyl]benzylacrylamide
• pigments e.g. titanium dioxides, zirconium dioxides, iron oxides, silicon dioxides, manganese oxides, aluminum oxides, cerium oxides or zinc oxides.
• the lipid phase in the cosmetic and/or dermatological preparations according to the invention can advantageously be chosen from the following groups of substances: mineral oils (advantageously paraffin oil), mineral waxes, hydrocarbons (advantageously squalane or squalene), synthetic or semisynthetic triglyceride oils (e.g. triglycerides of capric or caprylic acid), natural oils (e.g. castor oil, olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, borage seed oil and the like), natural ester oils (e.g.
• ester oils preferably esters of saturated and/or unsaturated, linear and/or branched alkanecarboxylic acids having 3 to 30 carbon atoms with saturated and/or unsaturated, linear and/or branched alcohols having 3 to 30 carbon atoms and esters of aromatic carboxylic acids with saturated and/or unsaturated, linear and/or branched alcohols having 3 to 30 carbon atoms, in particular chosen from the group consisting of isopropyl myristate, isopropyl stearate, isopropyl palmitate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl laurate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laureate, 2-hexyldecy
• alkyl benzoates e.g. mixtures of n-dodecyl, n-tridecyl, n-tetradecyl and n-pentadecyl benzoate
• cyclic or linear silicone oils such as, for example, dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof.
• the aqueous phase of the cosmetic and/or dermatological preparations according to the invention optionally advantageously comprises alcohols, diols or polyols of low carbon number, and ethers thereof, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl ether, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products, and also alcohols of low carbon number, e.g.
• ethanol isopropanol, 1,2-propanediol, glycerol, and also ⁇ - or ⁇ -hydroxy acids, preferably lactic acid, citric acid or salicylic acid, and also emulsifiers which can advantageously be chosen from the group of ionic, nonionic, polymeric, phosphate-containing and zwitterionic emulsifiers, and in particular one or more thickeners which can advantageously be chosen from the group consisting of silicon dioxide, aluminum silicates, such as, for example, bentonites, polysaccharides and derivatives thereof, e.g.
• hyaluronic acid guar kernal flour, xanthan gum, hydroxypropylmethylcellulose or allulose derivatives, particularly advantageously from the group of polyacrylates, preferably a polyacrylate from the group of carbopols, in each case individually or in combination or from the group of polyurethanes.
• a particularly advantageous embodiment of the present invention is regarded as being the use of the cosmetic or dermatological preparations according to invention comprising an effective constituent of the 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention for protecting tissues and cells of mammals, in particular of the skin and/or the hair, against oxidative stress and the harmful effect of free radicals.
• the present invention likewise also relates to a process for protecting cosmetic or dermatological preparations, and food and luxury products, against oxidation or photooxidation, the constituents of which are subject to stability problems due to oxidation or photooxidation during storage, characterized in that the preparations have an effective content of 3,4-dihydroxybenzyl-substituted carbonic acid derivatives according to the invention.
• the mixture was then stirred for a further 1.5 h at room temperature, converted to pH 1-2 with 5% strength H 2 SO 4 , extracted with tert-butyl methyl ether (3 ⁇ 20 ml), the combined organic phase was washed with saturated NaCl solution, dried over Na 2 SO 4 and filtered, and the filtrate was concentrated by evaporation at 45° C./20 mbar (2.81 g).
• the crude product was dissolved in 1,4-dioxane (10 ml) and water (20 ml) saturated NaHCO 3 solution (1 ml) was added and the mixture stirred at 80° C. for 2 h.
• reaction mixture was converted to pH 4 with 5% strength H 2 SO 4 , extracted with tert-butyl methyl ether (3 ⁇ 20 ml), the combined organic phase was washed with saturated NaCl solution, dried over Na 2 SO 4 and filtered, and the filtrate was concentrated by evaporation at 50° C./20 mbar (1.89 g).
• Part A was mixed and heated to 80° C.
• Part B was mixed and heated to 90° C. and added to part A with stirring.
• part C Carbopol was carefully dispersed in water and neutralized with sodium hydroxide solution (pH 5.4). Part C was then added to the mixture of parts A and B at 60° C.
• part A all the substances apart from the zinc oxide were heated to 85° C. and the zinc oxide was carefully dispersed in the mixture.
• the components of part B were mixed, heated to 85° C. and added to part A with stirring.
• Part C was added to the mixture of parts A and B and then the mixture was homogenized with a dispersion tool.
• part A all of the substances apart from the titanium dioxide were mixed and heated to 85° C.; the titanium dioxide was carefully dispersed into the mixture.
• part B all of the substances apart from Veegum and Natrosol were mixed, heated to 90° C., Natrosol and Veegum were dispersed therein and the mixture was added to part A with stirring.
• Part C was added to the mixture of parts A and B and then the mixture was homogenized using a dispersion tool (pH 5.6).
• Part A was heated to 85° C.
• Part B Carbopol and Keltrol were dispersed into the remaining constituents in the cold, the mixture was heated to 85° C. and added to part A.
• Part C was immediately added to the mixture of parts A and B at 80° C. and homogenized for 5 min with a dispersion tool.
• part D was added at room temperature and the mixture was homogenized using a dispersion tool (pH 6.6).
• DPPH was dissolved in methanol to a concentration of 100 ⁇ mol/l.
• a series of dilutions of the exemplary compounds, vitamin C, ⁇ -tocopherol and 3,5-di-tert-butyl-4-hydroxytoluene were prepared in methanol. Methanol served as the control.
• 2500 ⁇ l of the DPPH solution were mixed with 500 ⁇ l of each test solution and the decrease in absorption at 515 nm was read until the decrease was less than 2% per hour.
• the activity of the test substances as free-radical scavengers was calculated according to the following equation:
• Activity as free-radical scavenger (%) 100 ⁇ (absorption of the test compounds)/(absorption of the control) ⁇ 100.
• the activity of the exemplary compounds as antioxidants was compared with that of conventional antioxidants.
• the test system used was the accelerated autoxidation of lipids by air with or without antioxidant using the Rancimat apparatus (Rancimat is a registered trademark of Metrohm AG, Herisau, Switzerland).
• AOI IP (with test solution) /IP (control sample) .
• test Test compound (example number) substance N-(3,4-Dihydroxybenzyl)-O-methylurethane (1) 34 N-(3,4-Dihydroxybenzyl)-O-[(1R,3R,4S)menthyl] 48 urethane (2) N-(3,4-Dihydroxybenzyl)-O-hexylurethane (3) 49 N-(3,4-Dihydroxybenzyl)-O-(2-ethylhexyl)urethane (4) 45 N-(3,4-Dihydroxybenzyl)-N′-(n-hexyl)thiourea (5) 62 Vitamin C 0.7 ⁇ -Tocopherol 39 3,5-Di-tert-butyl-4-hydroxytoluene 38
• solution A A 0.2% strength ethanolic solution of tocopherol was prepared as internal standard (solution A).
• a dose of 2 mg/cm 2 of the formulation from Example 7 was applied twice daily to the skin on the backs of 12 subjects for 2 days in each case.
• solution A Prior to the subsequent irradiation, solution A was applied to a control area (2 mg/cm 2 ).
• the 2 treated and one untreated sites were irradiated with ultraviolet light (320 to 400 nm, 10 joules/cm 2 ).
• the test areas in each case were treated with 4 ml of ethanol for 2 min, the solutions were dried under nitrogen at room temperature and the residue was taken up in 1 ml of ethanol.
• % inhibition 100 ⁇ ( c SQOOH, untreated ⁇ c SQOOH, treated )/ C SQOOH, untreated

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